To determine the role of
apolipoprotein E (
apoE) in diabetic
hyperlipidemia, we induced diabetes in transgenic mice overexpressing
apoE by
intravenous injection of
streptozotocin (STZ) and examined plasma
lipoprotein metabolism in these mice. In STZ-induced diabetic mice,
blood glucose levels were > 19 mmol/l (350 mg/dl) and plasma
insulin levels were reduced to < 5 pmol/l (1 microU/ml). The diabetic nontransgenic mice developed
hypercholesterolemia (plasma total
cholesterol level: 4.55 +/- 1.32 vs. 1.97 +/- 0.13 mmol/l [176 +/- 51 vs. 76 +/- 5 mg/dl]) and
hypertriglyceridemia (plasma
triglyceride level: 0.82 +/- 0.29
vx. 0.42 +/- 0.11 mmol/l [73 +/- 26 vs. 37 +/- 10 mg/dl]) compared with values before induction of diabetes. In the diabetic nontransgenic mice, enhanced intestinal acylCoA:
cholesterol acyltransferase activity was demonstrated,
a factor that may contribute to the development of diabetic
hyperlipidemia. Induction of
apoE remarkably reduced the development of
hyperlipidemia in diabetic transgenic mice compared with diabetic nontransgenic mice (plasma
cholesterol level: 4.55 +/- 1.32 vs. 3.31 +/- 0.47 mmol/l [176 +/- 51 vs. 128 +/- 18 mg/dl], P < 0.01, and plasma
triglyceride level: 0.82 +/- 0.29 vs. 0.17 +/- 0.11 mmol/l [73 +/- 26 vs. 15 +/- 10 mg/dl], P < 0.01). Plasma
lipoprotein analysis by gel filtration chromatography showed that the reduction of plasma
cholesterol and
triglyceride levels was due to the disappearance of
lipoproteins containing
apoB. In these studies, we demonstrated the usefulness of STZ-induced diabetes in mice as an animal model for diabetic
hyperlipidemia and demonstrated that endogenous induction of
apoE in transgenic mice improved diabetic
hyperlipidemia.